Abstract
Valproic acid (VPA) is a frequently prescribed anti-epileptic drug which is known to cause liver toxicity and steatosis through mitochondrial dysfunction. Nevertheless the mechanisms underlying these adverse effects are incompletely understood. In this study, we determined the effect of relatively short (3 h) or prolonged (72 h) exposure to VPA on mitochondrial function in primary human hepatocytes (PHHs). While 3 h VPA exposure did not affect oxygen consumption rates (OCRs) in PHHs, prolonged exposure (24–72 h) significantly reduced basal and maximal OCRs. Given that in particular prolonged VPA exposure is required to cause mitochondrial dysfunction, we investigated gene expression data after VPA exposure for 24, 48, 72 h and 72 h VPA followed by a 72 h washout period. We were able to reduce the comprehensive gene expression changes into a more comprehensible set of 18 TFs that were predicted to be persistently activated after 72 h of VPA exposure. Lentiviral knock-down of one of the candidate TFs, C/EBPα, partly rescued VPA-induced mitochondrial dysfunction. Furthermore, RNA-Seq analysis of shC/EBPα and shGFP control PHHs identified 24 genuine C/EBPα target genes that are regulated in response to prolonged VPA exposure in PHHs. Altogether this provides new insights on the involvement of C/EBPα in driving VPA-induced mitochondrial dysfunction in human liver cells. This hub gene, with its downstream regulators involved in this deregulation, thus represent potential new biomarkers for VPA-induced mitochondrial dysfunction.
Highlights
Valproic acid (VPA) is one of the most widely prescribed drugs for epilepsy
Prolonged exposure (24–72 h) to 30 mM VPA was profoundly more potent in reducing basal respiration compared to 25 or 50 mM VPA for a short period of 3 h. All together these results demonstrate that chronic, daily exposure, to VPA but not a short 3 h exposure, leads to reduced oxygen consumption rates (OCRs) in primary human hepatocytes (PHHs) cells
Our data suggests that the transcription factor C/EBPα orchestrates gene expression changes upon prolonged VPA treatment (3 days) that contribute to mitochondrial dysfunction
Summary
Valproic acid (VPA) is one of the most widely prescribed drugs for epilepsy. Despite its therapeutic potency, prolonged VPA exposure can induce hepatoxicity which may progress into more severe liver injury. VPA is a simple fatty acid that is almost entirely metabolized by the liver via several mechanisms, including cytochrome P-450-mediated metabolism, glucuronidation and mitochondrial β-oxidation (Silva et al 2008). Hallmarks of VPA-induced hepatoxicity include disruption of mitochondrial β-oxidation, reduction. The enzyme carnitine palmitoyltransferase 1 (CPT1) plays a key role in this process by shuttling fatty acid-CoA into the mitochondria. CPT1 is affected by the majority of steatohepatitis-inducing drugs. Demonstrate an association between steatosis and mitochondrial dysfunction, which is thought to be mainly due to disrupted β-oxidation (Cengiz et al 2000; Fromenty et al 1997; Lheureux and Hantson 2009; Pessayre et al 1999; Tong et al 2005)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
